Pharmaceutical compositions comprising a statin and a cannabinoid and uses thereof

ABSTRACT

The invention relates to pharmaceutical compositions comprising a statin and a cannabinoid, and their use for the treatment of hypercholesterolemia and atherosclerosis. It has been found that compositions combining a statin and a cannabinoid are improved over existing statin formulations. The compositions of the invention for example allow for a lower effective dose of statin and a reduction of the adverse effects seen with statins taken alone. Dosing ranges and formulations suitable for oral, buccal, and sublingual administration are disclosed. Various specific cannabinoids such as cannabidiol and synthetic cannabidiols selected for their anti-inflammatory, antioxidant, and anti-atherosclerotic effect are shown to be particularly advantageous.

CROSS REFERENCE

This application is a U.S. national phase application under 35 U.S.C. §371 of co-pending International Application No. PCT/US17/54685, filed onOct. 1, 2017, which claims the benefit of U.S. Provisional ApplicationNo. 62/403,067, filed Oct. 1, 2016, which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The present invention generally relates to pharmaceutical compositionscomprising a statin and a cannabinoid which may be used in the treatmentof subjects with elevated cholesterol levels.

BACKGROUND OF THE INVENTION

Cholesterol is a waxy, fat-like substance that is naturally found in thebloodstream and in all cells of the human body, and is needed for thebody to function normally. However, the presence of abnormally highlevels of cholesterol in the blood, known as hypercholesterolemia, is amajor risk factor for heart disease and stroke. Indeed, people with highcholesterol have approximately twice the risk of acquiring heartdisease, the leading cause of death for both men and women in the UnitedStates.

Cholesterol travels through the bloodstream in small packages calledlipoproteins, which take two forms: low-density lipoproteins (LDL) andhigh-density lipoproteins (HDL). High levels of LDL cholesterol inparticular (referred to as “bad cholesterol”) increases the risk ofheart disease and stroke by causing arterial plaque buildup(“atherosclerosis”). By contrast, HDL cholesterol (or “goodcholesterol”) absorbs and carries cholesterol to the liver, which aidsin flushing it from the body. According to statistics from the Centersfor Disease Control and Prevention (CDC), over one-third of Americanadults have elevated levels of LDL cholesterol.

Although the atherosclerotic progression is not fully understood, it isbelieved to be caused by inflammatory processes resulting in part fromretained LDL cholesterol, which becomes prone to oxidation when insidearterial walls. The oxidation of LDL attracts white blood cells (WBCs),which penetrate into the arterial walls and transform into macrophages.The macrophages scavenge for and absorb the oxidized LDL, and form “foamcells,” which attempt to recruit HDL particles to process the LDLparticles and remove the fats. But if the level of LDL particles is toohigh relative to the level of HDL particles, foam cells cannot processall of the oxidized LDL, and will eventually die and burst, leavingbehind cholesterol and other debris in the artery wall. This attractsadditional WBCs, creating a feedback loop that results in furtherinflammation, and eventually an accumulation of material (a “plaque”).If a plaque ruptures, it can lead to the occlusion of blood vessels,cutting off blood supply, and potentially causing a heart attack orstroke. Reducing LDL cholesterol is therefore viewed as a key topreventing or slowing the progression of atherosclerosis, and loweringthe likelihood of related cardiovascular incidents.

Besides lifestyle changes, such as a modified diet and increasedphysical exercise, the primary form of treatment for high LDLcholesterol is the administration of drugs from the class known asHMG-CoA reductase inhibitors, commonly referred to as “statins.”

Statins

Statins work by inhibiting the HMG-CoA reductase enzyme, which plays acentral role in the production of cholesterol in the liver and producesabout 70% of total cholesterol in the body. By decreasing the liver'sproduction of cholesterol, statins lower total blood cholesterol and LDLcholesterol. Statins also increase the liver's ability to remove LDLcholesterol from the blood.

Various statins have been developed and brought to market, includingatorvastatin (Lipitor®, Pfizer), fluvastatin (Lescol®, Novartis),lovastatin (Mevacor®, Merck; Altoprev®, Andrex), pitavastatin (Livalo®,Kowa Pharms.), pravastatin (Pravachol®, Bristol-Myers Squibb),rosuvastatin (Crestor®, Astra Zeneca), and simvastatin (Zocor®, Merck).

Statins lower LDL cholesterol levels more than any other current drugtherapy, and are the most effective medications presently used formanaging elevated LDL cholesterol. Nonetheless, the use of statins totreat hypercholesterolemia suffers from significant drawbacks. Inobservational studies, 10-15% of people who take statins experiencemuscle problems, including such adverse effects as muscle discomfort andweakness, myositis (i.e., muscle inflammation) and rhabdomyolysis (i.e.,muscle breakdown). The incidence of such myopathic (i.e.,muscle-related) reactions increases with older age, use of interactingmedications such as fibrates, and hypothyroidism. Despite numerouspublications describing statin-induced myopathy, however, the mechanismhas not been elucidated.

Statin use also is correlated with an elevated risk of developing kidneyproblems. Statin use is associated with a 50% increase in risk of acuterenal failure, with evidence of raised risk within the first year ofuse, and greater risk at increased dosages. The occurrence of kidneyinjury could be related to the increased risk of muscle damage whentaking statins. Breakdown products of damaged muscle cells are releasedinto the bloodstream, and some of these, such as the protein myoglobin,are harmful to the kidneys and may lead to kidney failure. Additionally,statins have been shown to block the production of coenzyme Q10 (asubstance in the body that helps break down food), which also may leadto kidney injury. Other serious adverse effects of statin use includeliver injury, increased risk of diabetes mellitus, cognitive impairment,neuropathy, pancreatic dysfunction, and sexual dysfunction.

All commonly used statins have been shown to cause similar adverseeffects, although rates of those adverse effects can differ across theclass. Some researchers have suggested that hydrophilic statins (such asfluvastatin, rosuvastatin, and pravastatin) are less toxic thanlipophilic statins (such as atorvastatin, lovastatin, and simvastatin),but other studies have not found a connection. The risk of myopathy hasbeen suggested to be lowest with pravastatin and fluvastatin, possiblybecause they are more hydrophilic and as a result have less musclepenetration. Users of certain “high potency” statins (i.e., ≥10 mg perday rosuvastatin, ≥20 mg per day atorvastatin, and ≥40 mg per daysimvastatin) were shown to be 34% more likely to be hospitalized withacute kidney injury within 120 days after starting treatment compared to“low potency” statins. (Dormuth et al., Use of high potency statins andrates of admission for acute kidney injury, BMJ 2013.) One statin,cerivastatin (Baycol®/Lipobay®, Bayer) was withdrawn from the market in2001 following 52 deaths attributed to kidney failure from drug-relatedrhabdomyolysis, a rate that was ten times more common than with otherapproved statins, and greatest in patients on the highest (0.8 mg/day)dose of cerivastatin, and in patients who took gemfibrozil and otherfibrates concomitantly.

Different approaches have been attempted to reduce the adverse effectsof statins. For example, some newer statins, characterized by longerpharmacological half-lives and more cellular specificity, have beenshown to have a better ratio of efficacy to adverse effect rates.Nevertheless, the occurrence of serious adverse effects has not yet beeneliminated nor reduced satisfactorily. Indeed, for some patientsexperiencing statin-associated adverse effects, physicians may simplydecrease the dose or discontinue statin therapy altogether. However,this limits effective treatment and puts patients at increased risk ofcardiovascular morbidity and mortality. (Rosenson et al., Identificationand Management of Statin-Associated Symptoms in Clinical Practice,Cardiovasc. Drugs Ther., 31:187-95 (2017) at 188, 194, and referencescited.)

Therefore, a need continues to exist for therapeutically effectivepharmaceutical compositions for the treatment of hypercholesterolemiathat do not have the drawbacks of current treatment regimens withstatins, A significant advancement in the art would occur with thedevelopment of such pharmaceutical compositions. The subject of thepresent invention is a novel approach involving pharmaceuticalcompositions that combine a statin with a cannabinoid, such as thecannabinoid known as cannabidiol (CBD).

Cannabinoids

Cannabinoids are a diverse class of small molecules that are groupedtogether because of their ability to act on cannabinoid receptors foundin the brain and throughout the central and peripheral nervous systemsof humans and other mammals. Cannabinoid receptors are a class of cellmembrane receptors under the G protein-coupled receptor superfamily.There are two primary known types of cannabinoid receptors, known ascannabinoid 1 (CB₁) and cannabinoid 2 (CB₂). CB₁ receptors are foundprimarily in the central nervous system (i.e., the brain and spinalcord), as well as in the lungs, liver and kidneys. CB₂ receptors arefound primarily in the immune system and in hematopoietic cells.Cannabinoids also activate another G protein-coupled receptor known asGPR55, and are thought to activate GPR119 and GPR18.

Cannabinoids produced endogenously in humans and other mammals aretermed endocannabinoids. Taken together, these endocannabinoids and theendogenous cannabinoid receptors they act on (along with the enzymes fortheir synthesis and degradation) form the endocannabinoid system. Theendocannabinoid system has been shown or suggested to be involved in avariety of physiological processes including appetite, digestion,pain-sensation, mood, memory, reproduction, stress response, immunefunction, thermoregulation, energy balance, and sleep.

Cannabinoids also have been isolated from plants, including at least 85from the Cannabis plant, among other plants including echinacea, kava,tea, and flax. Cannabinoids from plants are termed phytocannabinoids.These non-endogenous cannabinoids also act on cannabinoid receptors inthe body, and they have many structural similarities with endogenouscannabinoids, and likewise have the ability to easily cross theblood-brain barrier, and show weak toxicity and few side effects. Amongthe naturally-occurring phytocannabinoids from cannabis,tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN) arethe three major constituents.

Tetrahydrocannabinol (THC) is one of the most widely-known cannabinoidsderived from the Cannabis plant, particularly because of itspsychoactive effects. The psychoactive effects of THC are thought to beprimarily because of its interaction with CB₁ receptors. Besides theprinciple THC isomer (−)-trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC),numerous other double bond and stereo isomers of THC have been derivedfrom Cannabis.

Cannabidiol (CBD), unlike THC, does not produce psychoactive effects inhumans (and in fact, can antagonize those effects). CBD is reported todemonstrate numerous pharmacological properties. For instance, CBD hasbeen shown to exert analgesic, antioxidant, anti-inflammatory,antiemetic, anticonvulsant, antipsychotic, anxiolytic, antidepressant,anticompulsive, antitumoral, neuroprotective, and immunomodulatoryeffects. CBD acts as an indirect antagonist of CB₁ and CB₂ cannabinoidreceptor agonists, and is also an inverse agonist of CB₂ receptors. CBDalso acts as an antagonist to other ligands at CB₁ and CB₂ receptors.Interaction with CB₂ receptors appears to be primarily responsible forthe anti-inflammatory and other therapeutic effects of cannabis seen inanimal models.

Numerous mechanisms of action supporting the pharmacological effects ofCBD have been demonstrated or suggested. For example, mechanisms thathave been shown or suggested to be related to the actions of CBD includeactivation of TRPV1 channels, inhibition of uptake and metabolism of theendocannabinoid anandamide, inhibition of adenosine uptake, antagonismof GPR55, agonism of PPARγ and 5-HT_(1A) receptors, and increase ofintracellular calcium ions. CBD also has been shown or suggested to berelated to reductions in mitochondrial superoxide generation, NF-κBactivation, levels of tumor necrosis factor (TNF) alpha and induciblenitric oxide synthase (iNOS), adhesion molecule expression,monocyte-endothelial adhesion, trans-endothelial migration of monocytes,disruption of endothelial barrier function in human coronary arteries,and reduction in cardiac cell death. Lymphoid cells that are importantactivators of macrophages and T-cells secrete less interferon-gamma andproliferate more slowly. Macrophage infiltration, a crucial step for thedevelopment of atherosclerosis, is inhibited in vitro. CBD protectscells against oxidative stress by decreasing the production of reactiveoxygen species (ROS) and, in particular central neurons, from apoptosis(programmed cell death).

The third major naturally-occurring phytocannabinoid in Cannabis plants,cannabinol (CBN), is weakly psychoactive, and found only in traceamounts. CBN has been shown to have analgesic properties but otherwiseis thought to exert minimal pharmacological effects in the centralnervous system. CBN has an affinity to CB₂ receptors, and also acts as apartial agonist of CB₁ receptors (but with lower affinity than THC).

Other naturally-occurring phytocannabinoids in Cannabis plants include,among numerous more, cannabigerol (CBG), cannabinodiol (also known ascannabidinodiol) (CBDL, CBND), cannabichromene (CBC), cannabielsoin(CBE), cannabicyclol (CBL), cannabicitran (CBT), cannabivarin (CBV),cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabichromevarin(CBCV), cannabigerovarin (CBGV), and cannabigerol monomethyl ether(CBGM).

Synthetic cannabinoids are compounds which have been made in alaboratory by means of chemical synthesis. Synthetic cannabinoids mayhave the same structure as endocannabinoids or phytocannabinoids, or mayhave modifications, including those resulting in or designed to causealterations in the way the cannabinoids function and behave. Numeroussynthetic variants and analogues of cannabinoids have been created, andsome have been shown to have altered or enhanced activity. For example,Breuer et al. (Fluorinated Cannabidiol Derivatives: Enhancement ofActivity in Mice Models, PLOS ONE, 2016) report the synthesis of threefluorinated CBD derivatives, one of which showed considerably greaterpotency than CBD in behavioral assays in mice predictive of anxiolytic,antidepressant, antipsychotic, and anticompulsive activity.

Cannabinoids also may be obtained from bioengineered organisms, such asbacteria or yeast. For example, yeast can be bioengineered to producecannabinoids by inserting genes that produce the appropriate enzymesand/or by altering the natural metabolic pathway to achieve theproduction of a desired compound from sugars, the main carbon sourceavailable to yeast. These compounds can then be obtained and purified.Through such means, cannabinoids may be obtained that are the same asthose extracted from Cannabis plants, or that are modifications thereof.

Drug Bioavailability and Metabolism

Bioavailability of a drug refers to the fraction of an administered doseof the drug that reaches the systemic circulation; that is, theproportion of the total dose that enters the bloodstream and is able toproduce an effect (typically calculated as the AUC, or “area under thecurve,” on a plot of the concentration of the drug in the blood overtime). By definition, when a drug is administered intravenously, itsbioavailability is 100%, because it is administered directly into thebloodstream. By comparison, when drugs are administered via other routes(such as orally), their bioavailability generally decreases. This is dueto incomplete absorption and first-pass metabolism (i.e., metabolismthat occurs before a drug reaches systemic circulation).

The metabolism of drugs inside living organisms involves a series ofchemical reactions organized into metabolic pathways, in which the drugis broken down through a series of steps into other chemicals, by asequence of specialized enzymes. The enzymes act as catalysts thatregulate the reactions and allow them to proceed more rapidly. The rateof metabolism in part determines the duration and intensity of a drug'spharmacologic action, because of its effect on drug bioavailability.

Cytochrome P450 proteins (abbreviated as CYPs) are a superfamily of over21,000 distinct enzymes found in virtually all organisms. CYPs in humansare found in the intestines and liver, and catalyze many reactionsinvolved in drug metabolism (and also play a role in the synthesis ofsteroids, cholesterol, and other lipids). The human CYP3A subfamily isinvolved in the metabolism of more than 50% of drugs clinically used,with CYP3A4 in particular being the most abundant isoform expressed inadult human livers.

CYP enzymes are responsible for the presystemic metabolism of certainstatins in the intestines and liver. Lovastatin, simvastatin, andatorvastatin are all substrates for CYP3A4 (as well as the withdrawnstatin cerivastatin, and mevastatin, which was never marketed).Lovastatin and simvastatin undergo extensive (90% or more) metabolism byCYP3A4, resulting in very low bioavailability. Atorvastatin does notundergo as extensive presystemic metabolism, and hence itsbioavailability is relatively higher.

Other statins are metabolized by different CYP enzymes, such asrosuvastatin (CYP2C9 and CYP2C19), pitavastatin (CYP2C9), andfluvastatin (primarily CYP2C9, and to a lesser degree CYP2C8 andCYP3A4), or by a different enzymatic system entirely (pravastatin,metabolized by sulfation). Although these different CYP enzymes are notas involved in drug metabolism as CYP3A4, they still play an importantrole for many drugs (with CYP2C19, for instance, acting on over 10% ofdrugs in clinical use).

It is commonly understood that the risk of certain adverse events mayincrease when a statin is taken together with another compound that isalso a substrate for or inhibitor of the same CYP enzymes. Bycompetitively binding to the same CYP enzymes as the statin, orotherwise inhibiting the ability of those CYP enzymes to bind with thestatin, the other compound decreases the rate of metabolism of thestatin, and consequently increases its bioavailability. For example,potent CYP3A4 inhibitors such as itraconazole (an antifungal medication)can produce two- to four-fold increases in atorvastatin serumconcentrations, and 10- to 20-fold increases in lovastatin andsimvastatin serum concentrations.

Increases in the bioavailability of the statin can result in increasedrisk of adverse events. For instance, the risk of statin-associatedmyopathy with lovastatin, simvastatin, and to a lesser extentatorvastatin, is increased by concomitant therapy with the macrolideantibiotics erythromycin and clarithromycin because of their CYP3A4metabolism and resultant increase in statin bioavailability. Increasedbioavailability along with myositis and rhabdomyolysis also have beenreported following concurrent use of simvastatin or lovastatin withcyclosporine A, mibefradil, and nefazodone. The calcium-channel blockerverapamil, another CYP3A4 inhibitor, is also known to increase the riskof statin-associated myopathy. And as noted above, theCYP3A4-metabolised statin cerivastatin was withdrawn from the marketbecause of the increased risk of kidney failure from drug-relatedrhabdomyolysis, a risk that was highest in patients who took it togetherwith fibrates (such as gemfibrozil) which are also substrates forCYP3A4. Similar interactions occur with statins that are metabolized byother CYP enzymes and the compounds that compete for or inhibit theactivity of those enzymes.

The metabolism of CBD administered orally is comprised of four primarysystems: the enzymes of the gastrointestinal lumen, gut wall enzymes,bacterial enzymes, and hepatic enzymes. The hepatic metabolism for CBDoccurs at CYP3A4, and to a lesser extent, CYP2C19. As a result of thismetabolic activity, the bioavailability of CBD administered orally inhumans is relatively poor, being approximately 6%. In addition to beingmetabolized by CYP3A4 and CYP2C19 enzymes in the liver, CBD alsofunctions as a potent inhibitor of those enzymes (see Yamaori et al.,Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol,Life Sci., 88:730-36 (2011); Jiang et al., Cannabidiol is a potentinhibitor of the catalytic activity of cytochrome P450 2C19, Drug Metab.Pharmacokinet., 28(4):332-38 (2013)). CBD is also a potent inhibitor ofvarious other CYP enzymes, including CYP2C9 (see Jiang at 333 andreferences cited).

Just as compounds which affect CYP3A availability will affect thebioavailability of CYP3A-metabolized statins, by the same token,compounds which affect CYP3A availability will affect CBDbioavailability. For example, the antifungal medication ketoconazole, astrong inhibitor of CYP3A4, has been demonstrated to increase the plasmaconcentration of CBD by about two-fold; while the antibiotic rifampin, aCYP3A4 inducer, reduced CBD levels by 50-60%. Other CYP3A4 inhibitorsand inducers would be expected to have a similar effect on CBD plasmaconcentrations if coadministered. The same would be true with inhibitorsand inducers of other CYP enzymes, such as CYP2C19 and CYP2C9.

Despite such generalized knowledge and use of statins and cannabinoids,the teachings demonstrating the use of statins for treatment of highcholesterol, along with the teachings demonstrating the properties ofcannabinoids such as CBD, could not have predicted the benefits thatcould be achieved by administration of a statin and a cannabinoid incombination, as in the pharmaceutical compositions of the presentinvention. Indeed, knowledge that the risk of adverse events mayincrease when a statin is taken together with another compound that isalso a substrate for or inhibitor of the same CYP enzymes would haveeffectively taught away from the combination of a cannabinoid and astatin; whereas the present invention discloses unexpectedly that such acombination in fact can reduce the number and severity of adverseevents.

INCORPORATION BY REFERENCE

Each patent, publication, and non-patent literature cited in theapplication is hereby incorporated by reference in its entirety as ifeach was incorporated by reference individually.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide pharmaceuticalcompositions comprising a pharmaceutically effective amount of a statin,in combination with such other compounds so as to convey or enhance theantihypercholesterolemic effect of the statin while preferably alsoreducing or eliminating the drawbacks of current treatment regimens withstatins.

It is an object of the present invention to provide such pharmaceuticalcompositions where the statin is combination with a cannabinoid.

In preferred embodiments, it is an object of the present invention toprovide pharmaceutical compositions where the statin is in combinationwith a cannabidiol.

In more preferred embodiments, it is an object of the present inventionto provide pharmaceutical compositions where the statin is incombination with Δ²-cannabidiol.

It is another object of the invention to provide pharmaceuticalcompositions of a statin and a cannabinoid that exhibit enhancedbioavailability of the statin.

In preferred embodiments, the bioavailability of both the statin and thecannabinoid are enhanced.

In other preferred embodiments, both the and the cannabinoid aresubstrates of the same CYP enzyme.

In more preferred embodiments, both the statin and the cannabinoid aresubstrates of CYP3A4.

In other more preferred embodiments, both the statin and the cannabinoidare substrates of CYP2C19 and/or CYP2C9.

In more preferred embodiments, the cannabinoid is a syntheticcannabidiol.

In still more preferred embodiments, the cannabinoid is a syntheticcannabidiol that shows enhanced inhibitory activity of the CYP3A4 enzymecompared to naturally-occurring cannabidiols.

In other more preferred embodiments, the cannabinoid is a syntheticcannabidiol that shows enhanced inhibitory activity of the CYP2C19and/or CYP2C9 enzyme compared to naturally-occurring cannabidiols.

In other more preferred embodiments, the cannabinoid is a syntheticcannabidiol that exhibits enhanced anti-inflammatory activity.

In other more preferred embodiments, the cannabinoid is a syntheticcannabidiol that exhibits enhanced antioxidant activity.

In other more preferred embodiments, the cannabinoid is a syntheticcannabidiol that exhibits enhanced anti-atherosclerotic activity.

In the most preferred embodiments, the cannabinoid is a syntheticcannabidiol that exhibits multidimensional enhanced activity, beingselected for possessing two or more of: enhanced CYP enzyme inhibitoryactivity; enhanced anti-inflammatory activity; enhanced antioxidantactivity; and enhanced anti-atherosclerotic activity.

In other preferred embodiments, the cannabinoid is obtained by means ofa bioengineered organism such as bacteria or yeast.

It is another object of the invention to provide commerciallypracticable pharmaceutical compositions of a statin and a cannabinoidthat are readily formulated and administered.

It is yet another object of the invention to provide pharmaceuticalcompositions of a statin and a cannabinoid that exhibit enhancedbioavailability of the statin, but where such increased bioavailabilityis without concomitant increases in the risk of myopathy or otherserious adverse effects.

It is another object of the present invention to provide dose ranges atwhich the pharmaceutical compositions of a statin and a cannabinoid(i.e., the “statin-cannabinoid compositions”) shall be therapeuticallyeffective.

It is an additional object of this invention to providestatin-cannabinoid compositions which comprise a cannabinoid in anamount effective to lower the effective dose of the selected statin.

It is another object of the present invention to providestatin-cannabinoid compositions in which the amount of cannabinoid iseffective to reduce the highest dosage of the statin by a measurableamount, such as 25%, 50%, or 75%, when compared to the highestrecommended dosage when the statin is administered alone, without anynoticeable loss of therapeutic effect.

It is another object of the present invention to provide a method oftreating a human with a statin-cannabinoid composition, in which theamount of cannabinoid is effective to reduce the dosage of the statin bya measurable amount, such as 25%, 50%, or 75%, relative to the previousprescribed dosage of the statin when administered alone, without anynoticeable loss of therapeutic effect.

It is an additional object of this invention to providestatin-cannabinoid compositions that safely allow for higher dosages ofthe selected statin without the risk (or with a substantially reducedrisk) of severe statin-induced adverse effects (e.g., myolysis orrhabdomyolysis).

In certain preferred embodiments, it is an additional object of theinvention to provide pharmaceutical compositions which are withoutpsychoactive effect.

It is an additional object of this invention to provide a method oftreating hypercholesterolemia in a subject, the method comprisingadministering to the subject a pharmaceutical composition of theinvention.

It is another object of the invention to provide a method of inhibitingcholesterol biosynthesis in a patient in need of such treatment byadministering an effective amount of a pharmaceutical composition asdefined herein.

It is an additional object of this invention to provide a method oftreating or preventing rhabdomyolysis or statin-associated myopathy in asubject, the method comprising administering to the subject apharmaceutical composition of the invention.

These and other objects, features, and advantages of the presentinvention may be more clearly understood and appreciated from a reviewof the following detailed description of the disclosed embodiments andby reference to the appended claims. The foregoing summary has been madewith the understanding that it is to be considered as a brief andgeneral synopsis of only some of the objects and embodiments, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

Definitions

The following definitions are provided to better elucidate the presentinvention and to guide those of ordinary skill in the art in thepractice of the present invention. Unless otherwise noted, terms are tobe understood according to conventional usage by those of ordinary skillin the relevant art.

“Botanical drug substance” is as defined in the Guidance for IndustryBotanical Drug Products, June 2004, US Department of Health and HumanServices, Food and Drug Administration Center for Drug Evaluation andResearch (“2004 FDA Botanical Drug Guidance”), i.e., “A drug substancederived from one or more plants, algae, or macroscopic fungi. It isprepared from botanical raw materials by one or more of the followingprocesses: pulverization, decoction, expression, aqueous extraction,ethanolic extraction, or other similar process. It may be available in avariety of physical forms, such as powder, paste, concentrated liquid,juice, gum, syrup, or oil. A botanical drug substance can be made fromone or more botanical raw materials. A botanical drug substance does notinclude a highly purified or chemically modified substance derived fromnatural sources.”

“Botanical drug product” is as defined in the 2004 FDA Botanical DrugGuidance, i.e., “A botanical product that is intended for use as a drug;a drug product that is prepared from a botanical drug substance.”

“Cannabinoid” refers to all naturally-occurring, synthetic, orbioengineered compounds that can mimic the behavior of endogenous orplant-derived cannabinoids (e.g., acting on CB₁, CB₂, and GPR55receptors), or that have structures that are modifications of endogenousor plant-derived cannabinoids, or are otherwise enantiomers, precursors,prodrugs, metabolites, derivatives, analogs, or variants thereof. Manysuch compounds have been described (see, e.g., U.S. Pat. Nos. 5,532,237;5,605,906; 5,631,297; 6,410,588; 6,610,737; 6,630,507 at cols.3:36-6:66; 6,274,635 at cols. 8:63-20:11; and 8,071,641 at cols.5:38-6:26; and references cited), and numerous other cannabinoids wouldbe recognized or known to those of ordinary skill in the art, or be ableto be created by the practice of ordinary skill in the art.

“Cannabidiol” or “CBD” refers to Δ²-cannabidiol (i.e.,2-[(1R,6R)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol),its seven double bond isomers and their 30 stereoisomers (see Nagaraja,Synthesis of delta-3-cannabidiol and the derived rigid analogs, Ariz.Univ. 1987), and such other naturally-occurring, synthetic, orbioengineered enantiomers, metabolites, derivatives, analogs, orvariants thereof as would be recognized or known to those of ordinaryskill in the art, or be able to be created by the practice of ordinaryskill in the art. Exemplary cannabidiols include those described in U.S.Pat. No. 6,274,635 at cols. 17:41-20:11; U.S. Pat. No. 7,759,526 atcols. 1:65-2:35; and U.S. Pat. No. 8,071,641 at cols. 6:36-7:25; andreferences cited. Within the scope of cannabidiols are also itsprecursors and prodrugs, for example those described in U.S. Pat. No.8,293,786, and the enantiomers, metabolites, derivatives, analogs, andvariants thereof.

“Cannabis-derived drug substance” means botanical drug substances whichare derived from Cannabis plants (including plant parts, plant partbiomass, and plant exudates), for example primary extracts prepared byprocesses including maceration, percolation, extraction with solventssuch as C1 to CS alcohols (e.g., ethanol), Norflurane (HFA134a), HFA227,liquid carbon dioxide under pressure and extraction using a hot gas.

“Cannabis-derived drug product” means a primary cannabis extract that isfurther purified, for example by supercritical or subcriticalextraction, vaporization and chromatography. It will be known to thoseof skill in the art that when solvents such as those listed above (see“Cannabis-derived drug substance”) are used to prepare primary extracts,the resultant extract may contain non-specific lipid-soluble material.Those of skill in the art will know that such impurities can be removedby a variety of processes including winterization (e.g., by chilling to−20° C. followed by filtration to remove waxy ballast), extraction withliquid carbon dioxide, and distillation.

“Cannabis plant” is defined to encompass all wild-type Cannabis saliva,Cannabis indica, and Cannabis ruderalis plants, as well as geneticcrosses, self-crosses, hybrids, variants, and chemovars thereof.

“Optional” or “optionally” means that the subsequently described eventor circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not.

“Pharmaceutically acceptable” as used in connection with an excipient,carrier, or diluent means an excipient, carrier, or diluent that isuseful in preparing a pharmaceutical composition that is generally safe,non-toxic and neither biologically nor otherwise undesirable forveterinary use and/or human pharmaceutical use.

“Psychoactive effect” means objectively or subjectively apparentalterations in behavior, perception, mood, or consciousness.

“Statin” means a drug from the class known as HMG-CoA reductaseinhibitors. Statins within the scope of this invention therefore includethose drugs which have already been developed and approved, for exampleatorvastatin (Lipitor®, Pfizer), fluvastatin (Lescol®, Novartis),lovastatin (Mevacor®, Merck; Altoprev®, Andrex), pitavastatin (Livalo®,Kowa Pharmaceuticals), pravastatin (Pravachol®, Bristol-Myers Squibb),rosuvastatin (Crestor®, Astra Zeneca), and simvastatin (Zocor®, Merck).Statins would be understood to include all dosage forms and formulationsof the above (e.g., immediate as well as extended release). Statins alsoshould be understood to include any other HMG-CoA reductase inhibitors,whether already known and characterized (such as mevastatin, velostatin,dihydrocompactin, dalvastatin, cerivastatin, carvastatin, crilvastatin,bevastatin, cefvastatin, and glenvastatin), currently in the developmentor approval process, or as yet to be developed, that function byinhibiting the HMG-CoA reductase enzyme, or otherwise function in a waythat is equivalent or understood to be equivalent by one of skill in theart. Statins shall also be understood to include allpharmaceutically-acceptable amorphous and crystalline forms and salts,esters, and lactone forms, for example as described for atorvastatin inU.S. Pat. App. No. 2003/0162827A1, and references cited.

“CYP3A4-metabolized statins” means those statins whose route ofmetabolization in the liver includes the Cytochrome P450 isoenzymeCYP3A4. Examples of CYP3A4-metabolized statins include lovastatin,simvastatin, and atorvastatin.

“CYP2C19-metabolized statins” means those statins whose route ofmetabolization in the liver includes the Cytochrome P450 isoenzymeCYP2C19. An example of a CY2C19-metabolized statin is rosuvastatin.

“CYP2C9-metabolized statins” means those statins whose route ofmetabolization in the liver includes the Cytochrome P450 isoenzymeCYP2C9. Examples of CYP3A4-metabolized statins include rosuvastatin,fluvastatin, and pitavastatin.

“Therapeutically effective amount” means the amount of a pharmaceuticalcomposition that, when administered to a patient for treating acondition, disorder, or disease, is sufficient to effect such treatmentfor the condition, disorder, or disease. The amount constituting a“therapeutically effective amount” of the present invention will varydepending on the statin and the cannabinoid used, the severity of thecondition, disorder, or disease, and the age, weight, and othermedically-relevant characteristics of the subject to be treated, andsuch a determination (if not already made) will be able to be renderedwithout undue experimentation by one of skill in the art.

“Therapeutic effect” means the responses(s) in a patient after treatmentwhich are judged to be desirable and beneficial. For treatment ofpatients having symptoms of hypercholesterolemia, such responses shallinclude, for example, reductions in total blood cholesterol, reductionsin LDL cholesterol, reductions in triglyceride levels, regression ofarterial atherosclerotic plaque, reduced risk of cardiovascular andcerebrovascular events, and other such measurements, benefits, andsurrogate or clinical endpoints, whether alone or in combination, aswould be understood to those of ordinary skill. Accordingly, “withoutloss of therapeutic effect” means that the observed response(s) in thepatient are not significantly diminished following a change in treatmentregimen, as would be understood to one of ordinary skill.

“Treating” “treatment” of a disease includes (i) inhibiting the disease,i.e., arresting or reducing the development of the disease or itsclinical symptoms; or (ii) relieving the disease, i.e., causingregression of the disease or its clinical symptoms. Inhibiting thedisease, for example, would include prophylaxis. Hence, one of skill inthe art will understand that a therapeutic amount necessary to effecttreatment for purposes of this invention will, for example, be an amountthat provides for objective indicia of improvement in patients havingsymptoms of hypercholesterolemia. Such indicia of improvement shallinclude, for example, reductions in total blood cholesterol, reductionsin LDL cholesterol, reductions in triglyceride levels, regression ofarterial atherosclerotic plaque, reduced risk of cardiovascular andcerebrovascular events, and other such measurements, benefits, andsurrogate or clinical endpoints, whether alone or in combination, aswould be understood to those of ordinary skill.

When introducing elements of the present invention or the preferredembodiments thereof, the articles “a,” “an,” “the,” and “said” areintended to mean that there are one or more of the elements. The terms“comprising,” “including,” and “having” are intended to be inclusive andnot exclusive (i.e., there may be other elements in addition to therecited elements).

DETAILED DESCRIPTION OF THE INVENTION

Among the various aspects of the present invention are pharmaceuticalcompositions comprising a statin, a cannabinoid, and apharmaceutically-acceptable carrier, diluent, or excipient. While thepresent invention is described in terms of particular embodiments andapplications, it is not intended that these descriptions in any waylimit its scope to any such embodiments and applications, and it will beunderstood that many modifications, substitutions, changes, andvariations in the described embodiments, applications, and details ofthe invention illustrated herein can be made by those skilled in the artwithout departing from the spirit of the invention, or the scope of theinvention as described in the appended claims.

Central to the present invention is the discovery that a statin taken incombination with a cannabinoid, such as a cannabidiol, will exhibit asynergistic effect. The present invention thus advantageously offerspharmaceutical compositions that are substantially improved overexisting statin formulations. For example, the statin-cannabinoidcompositions of the present invention enable a lower dose of statinwithout loss of therapeutic effect, and can reduce the number andseverity of adverse effects compared to statins used alone. Further, thespecific formulations of the invention provide for improvedbioavailability of the statin and cannabinoid used. Other features andadvantages will emerge from the following description of the invention.

Statin+Cannabinoid Combinations

The statins used in the pharmaceutical compositions of the presentinvention are preferably those that are commercially available andapproved for use in treating hypercholesterolemia. These includeatorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,rosuvastatin, and simvastatin.

Preferably, the statins used are CYP2C19-metabolized statins orCYP2C9-metabolized statins.

More preferably, the statins used are CYP3A4-metabolized statins.

More preferably still, the statins used are CYP3A4-metabolized statinsfrom the group consisting of atorvastatin, lovastatin, and simvastatin.

The cannabinoids used in the pharmaceutical compositions of theinvention are preferably one or more cannabidiols.

More preferably, the cannabinoids used shall be Δ²-cannabidiol, and morepreferably still, Δ²-cannabidiol that is synthetic or obtained throughbioengineered means.

More preferably still, the cannabinoids used shall be from the groupconsisting of synthetic cannabidiols selected for their CYP enzymeaffinity (e.g., their CYP3A4, CYP2C19, and/or CYP2C9 enzyme affinity),their anti-inflammatory, antioxidant, or anti-atherosclerotic effects,or a combination of such traits.

The cannabinoids used in the compositions of the invention may beobtained as natural compounds (e.g., as a Cannabis-derived drugsubstance or drug product), as synthetic compounds, from a bioengineeredorganism (e.g., bacteria or yeast), or as a combination thereof.

Thus, in one embodiment of the invention, the compositions shall bederived from Cannabis plants, by extraction or other means, and shallcomprise one or more cannabis-derived drug substances. Preferably, suchcompositions shall comprise one or more cannabis-derived drug products.More preferably, such compositions shall comprise one or morecannabis-derived drug products which are substantially free fromimpurities. Methods of extracting cannabinoids from Cannabis plants, andobtaining purified products containing the desired cannabinoids, freefrom psychoactive compounds such as THC, and free from other impurities,are known in the art and have been described in, e.g., U.S. Pat. Nos.6,403,126, 8,846,409 and 8,895,078; and U.S. Pat. App. Nos.2003/0017216A1 and 2016/0038437A1; including references cited.

In preferred embodiments of the invention, the compositions shallcomprise one or more synthetic cannabinoids. Preferably, suchcompositions shall comprise one or more synthetic cannabinoidssubstantially free from impurities. Synthetic cannabinoids may begenerated by means of chemical synthesis from commercially obtainable orotherwise readily available starting materials, using publishedprocedures, such as by way of the methods described in U.S. Pat. Nos.7,759,526 and 8,071,641, U.S. Pat. App. No. 2010/0298579A1, or by usingother methods known to those of ordinary skill in the art.

In other preferred embodiments of the invention, the compositions shallcomprise one or more cannabinoids obtained from a bioengineeredorganism, such as bacteria or yeast. Preferably, such compositions shallcomprise one or more bioengineered cannabinoids substantially free fromimpurities. Bioengineered organisms capable of producing desiredcannabinoids can be created, and the cannabinoids can be obtained andpurified therefrom, using methods known in the art; see, e.g., U.S. Pat.App. No. 2016/0010126A1.

In some preferred embodiments, the statin is chosen from the group ofCYP3A4-metabolized statins, and the cannabinoid is CBD. CBD is alsometabolized by CYP3A4 enzymes, as well as acting as a potent inhibitorof CYP3A4. Through both mechanisms CBD is able to displaceCYP3A4-metabolized statins and slow their metabolism, resulting in theirincreased bioavailability, and resulting in pharmaceutical compositionsof the invention that can advantageously treat patients withhypercholesterolemia at lower statin dosages and while reducing the riskof adverse effects. Methods of measuring statin and cannabinoidbioavailability have been discussed in, e.g., Huestis, Human CannabinoidPharmacokinetics, Chem. Biodivers., 8:1770-1804 (2007); and Garcia etal., Clinical Pharmacokinetics of Statins, Methods Find. Exp. Clin.Pharmacol., 6:457-81 (2003); and references cited.

Similarly, in other preferred embodiments, the statin is chosen from thegroup of CYP2C19-metabolized statins and CYP2C9-metabolized statins, andthe cannabinoid is CBD. CBD is also metabolized by CYP2C19 and CYP2C9enzymes, as well as acting as a potent inhibitor of those CYP enzymes.Through both mechanisms CBD is able to displace CYP2C19-metabolizedstatins and CYP2C9-metabolized statins and slow their metabolism,resulting in their increased bioavailability, and resulting inpharmaceutical compositions of the invention that can advantageouslytreat patients with hypercholesterolemia at lower statin dosages andwhile reducing the risk of adverse effects.

In more preferred embodiments, the statin is chosen from the group ofCYP3A4-metabolized statins, and the cannabinoid is a syntheticcannabinoid having increased affinity for the CYP3A4 enzyme. In yet morepreferred embodiments, the cannabinoid is a synthetic cannabidiol havingincreased affinity for the CYP3A4 enzyme. Although allnaturally-occurring cannabidiols, for example, are believed to inhibitthe CYP3A4 enzyme, certain synthetic cannabidiols exhibit strongerinhibitory activity when compared against them, and such compounds canbe used more advantageously in the pharmaceutical compositions of theinvention. Embodiments combining such higher potency cannabinoids withCYP3A4-metabolized statins will exhibit further enhancement of thebioavailability of the statin, as well as of the cannabinoids, as thecompetitive binding will reduce the metabolism of the cannabinoids byCYP3A4 as well. By using such higher potency cannabinoids, thepharmaceutical compositions of the invention can more advantageouslytreat patients with hypercholesterolemia at further reduced statindosages and while also further reducing the risk (in both number andseverity) of adverse effects. The evaluation of cannabinoid compoundsfor their potency as CYP3A4 inhibitors can be performed by using suchmethods as described in, e.g., Yamaori et al., Potent inhibition ofhuman cytochrome P450 3A isoforms by cannabidiol, Life Sci. 88:730-36(2011). These and other known methods can be used to compare the potencyof CYP3A4 inhibition, for example, of various synthetic cannabidiols toa set of naturally-occurring cannabidiols, or of various othercannabinoid compounds to a set of baseline cannabinoids, to selectspecific higher potency cannabinoids to be used in the practice of theinvention.

Similarly, in other more preferred embodiments, the statin is chosenfrom the group of CYP2C19-metabolized statins and CYP2C9-metabolizedstatins, and the cannabinoid is a synthetic cannabinoid having increasedaffinity for the CYP2C19 and/or CYP2C9 enzymes. In yet more preferredembodiments, the cannabinoid is a synthetic cannabidiol having increasedaffinity for the CYP2C19 and/or CYP2C9 enzymes. Although allnaturally-occurring cannabidiols, for example, are believed to inhibitthe CYP2C19 and CYP2C9 enzymes, certain synthetic cannabidiols exhibitstronger inhibitory activity when compared against them, and suchcompounds can be used more advantageously in the pharmaceuticalcompositions of the invention. Embodiments combining such higher potencycannabinoids with CYP2C19- and/or CYP2C9-metabolized statins willexhibit further enhancement of the bioavailability of the statin, aswell as of the cannabinoids, as the competitive binding will reduce themetabolism of the cannabinoids by those GYP enzymes as well. By usingsuch higher potency cannabinoids, the pharmaceutical compositions of theinvention can more advantageously treat patients withhypercholesterolemia at further reduced statin dosages and while alsofurther reducing the risk of adverse effects. The evaluation ofcannabinoid compounds for their potency as CYP2C19 inhibitors can beperformed by using such methods as described in, e.g., Jiang et al.,Cannabidiol is a potent inhibitor of the catalytic activity ofcytochrome P450 2C19, Drug Metab. Pharmacokinet., 28(4):332-38 (2013).These and other known methods can be used to compare the potency ofCYP2C19 and CYP2C9 inhibition, for example, of various syntheticcannabidiols to a set of naturally-occurring cannabidiols, or of variousother cannabinoid compounds to a set of baseline cannabinoids, to selectspecific higher potency cannabinoids to be used in the practice of theinvention.

In other preferred embodiments, the cannabinoid is a cannabinoidselected for its anti-inflammatory activity. In more preferredembodiments, the cannabinoid is a synthetic cannabidiol selected for itsanti-inflammatory activity. Although all naturally-occurringcannabidiols, for example, are believed to exhibit someanti-inflammatory activity, certain synthetic cannabidiols exhibitstronger anti-inflammatory activity when compared against them, and suchcompounds can be used advantageously in the pharmaceutical compositionsof the invention. These and other higher potency anti-inflammatorycannabinoids can be chosen to beneficially target both the inflammatorycascades at the root of atherosclerotic lesion development, as well asthe inflammatory responses responsible for certain adverse effects ofstatins therapy (e.g., myositis). By using such higher potencyanti-inflammatory cannabinoids, the pharmaceutical compositions of theinvention can advantageously treat patients with hypercholesterolemiawhile reducing the risk of adverse effects. Methods of evaluatingcannabinoid compounds for their potency to act as anti-inflammatoryagents are described in, e.g., PCT/GB1999/001140, PCT/IL1999/000187, andCalhoun W. et al, Agents and Actions, 21:306-09 (1987). These and otherknown methods can be used to compare the anti-inflammatory activity, forexample, of various synthetic cannabidiols to a set ofnaturally-occurring cannabidiols, or of various other cannabinoidcompounds to a set of baseline cannabinoids, to select specific higherpotency anti-inflammatory cannabinoids to be used in the practice of theinvention. For example, in Haj et al., HU-444, a Novel, PotentAnti-Inflammatory, Nonpsychotropic Cannabinoid, J. Pharm. (205), theauthors report on a synthetic CBD derivative demonstrating increasedactivity in in vitro and in vivo anti-inflammatory assays. Similarly, inXu et al., Anti-inflammatory property of the cannabinoidreceptor-2-selective agonist JWH-133, J. Leukocyte Bio. 3:532-41 (2007),the authors report on high in vivo anti-inflammatory activity of thesynthetic cannabinoid JWH 133.

In still more preferred embodiments, the statin is chosen from the groupof CYP3A4-, CYP2C19-, and CYP2C9-metabolized statins, and thecannabinoid is a synthetic cannabidiol that has greater affinity for thesame CYP enzyme(s), and also exhibits increased anti-inflammatoryactivity. In such embodiments, the pharmaceutical compositions of theinvention will be understood to be particularly advantageously used totreat patients with hypercholesterolemia while reducing the risk ofadverse effects.

In other preferred embodiments, the cannabinoid is a cannabinoidselected for its antioxidant potential. In more preferred embodiments,the cannabinoid is a synthetic cannabidiol selected for its antioxidantpotential. Although all naturally-occurring cannabidiols, for example,are believed to exhibit some antioxidant activity, and may thereforelimit disease progression in patients with hypercholesterolemia, certainsynthetic cannabidiols will exhibit stronger antioxidant potential whencompared against them, and such compounds can be used advantageously inthe pharmaceutical compositions of the invention. These and other higherpotency antioxidant cannabinoids can be chosen to provide additionaltherapeutic benefits to patients with hypercholesterolemia. By usingsuch higher potency antioxidant cannabinoids, the pharmaceuticalcompositions of the invention can advantageously treat patients withhypercholesterolemia while reducing the risk of adverse effects. Methodsof evaluating cannabinoid compounds for their potency to act asantioxidants are described in, e.g., Cassol et al., Treatment withcannabidiol reverses oxidative stress parameters, Brain Res. 1348:128-38(2010), and Rajesh et al., Cannabidiol attenuates cardiac dysfunction,oxidative stress, fibrosis, and inflammatory and cell death signalingpathways in diabetic cardiomyopathy, J. Am. Coll. Cardiol., 25:2115-25(2010). These and other known methods can be used to compare theantioxidant activity, for example, of various synthetic cannabidiols toa set of naturally-occurring cannabidiols, or of various othercannabinoid compounds to a set of baseline cannabinoids, to selectspecific higher potency antioxidant cannabinoids to be used in thepractice of the invention.

In other preferred embodiments, the cannabinoid is a cannabinoidselected for its anti-atherosclerotic potential. In more preferredembodiments, the cannabinoid is a synthetic cannabidiol selected for itsanti-atherosclerotic potential. Although all naturally-occurringcannabidiols, for example, are believed to exhibit someanti-atherosclerotic activity, and may therefore reduce the developmentof atherosclerosis, and limit disease progression in patients withhypercholesterolemia, certain synthetic cannabidiols will exhibitstronger anti-atherosclerotic potential when compared against them, andsuch compounds can be used advantageously in the pharmaceuticalcompositions of the invention. These and other higher potencyanti-atherosclerotic cannabinoids can be chosen to provide additionaltherapeutic benefits to patients with hypercholesterolemia. By usingsuch higher potency anti-atherosclerotic cannabinoids, thepharmaceutical compositions of the invention can advantageously treatpatients with hypercholesterolemia while reducing the risk of adverseeffects. Methods of evaluating cannabinoid compounds for their potencyto act as anti-atherosclerotic agents are described in, e.g., Steffenset al., Low dose oral cannabinoid therapy reduces progression ofatherosclerosis in mice, Nature 434:782-86 (2005). These and other knownmethods can be used to compare the anti-atherosclerotic activity, forexample, of various synthetic cannabidiols to a set ofnaturally-occurring cannabidiols, or of various other cannabinoidcompounds to a set of baseline cannabinoids, to select specific higherpotency anti-atherosclerotic cannabinoids to be used in the practice ofthe invention.

In still more preferred embodiments, the statin is chosen from the groupof CYP3A4-, CYP2C19-, and CYP2C9-metabolized statins, and thecannabinoid is a synthetic cannabidiol that has greater affinity for thesame CYP enzyme(s), and also exhibits two or more of: increasedanti-inflammatory activity, increased antioxidant activity, andincreased anti-atherosclerotic activity. In such embodiments, thepharmaceutical compositions of the invention will be understood to beparticularly advantageously used to treat patients withhypercholesterolemia while reducing the risk of adverse effects. Ingeneral, it should be understood that selecting for cannabinoids havinga combination of beneficial traits would be most advantageous in thepractice of the invention, and one would understand how to select forand obtain such cannabinoids, e.g., by using the methods described abovein serial (i.e., selecting for the desired traits successively) toevaluate target cannabinoids.

In certain preferred embodiments, it is an object of the invention thatthe pharmaceutical composition be without psychoactive effect. Methodsof measuring the psychoactive effects of cannabinoids will be known tothose of ordinary skill, and have been discussed in, e.g., Issa et al.,The Subjective Psychoactive Effects of Oral Dronabinol, Clin. J. Pain,30(6):472-78 (2014). Thus, in some preferred embodiments, thecannabinoid or cannabinoids used shall be substantially free of THC. Insuch embodiments, it is understood that the pharmaceutical compositionof the invention is therefore substantially free of THC. In morepreferred embodiments, the composition is entirely free of measurableTHC. In some preferred embodiments, the pharmaceutical composition doesnot produce any psychoactive metabolites. In these and otherembodiments, the pharmaceutical composition is without psychoactiveeffect when taken in a therapeutically active amount. In preferredembodiments, the pharmaceutical composition is without psychoactiveeffect even at dosages above the therapeutically effective amount.Methods of obtaining purified extracts from Cannabis plants containingthe desired cannabinoids free from psychoactive compounds such as THCare known in the art and have been described in, e.g., U.S. Pat. No.6,403,126. One of skill in the art also would understand that thedesired cannabinoids for the practice of the invention could be obtainedfree from THC and other psychoactive cannabinoids by obtaining themthrough chemical synthesis or from a bioengineered organism.

Excipients, Carriers, and Diluents

According to the present invention, the pharmaceutical compositioncomprises a pharmaceutically-acceptable excipient. Alternatively, thepharmaceutical composition may comprise a pharmaceutically-acceptablecarrier or diluent in addition to or in place of thepharmaceutically-acceptable excipient. Examples of excipients, carriers,and diluents that may be used in these compositions include foods,drinks, lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum,acacia, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, polyethylene glycol,cellulose, methyl cellulose, methylhydroxybenzoates,propylhydroxybenzoates, proplhydroxybenzoates, talc, petroleum, andmineral oil. In preferred embodiments, polymeric excipients shall beused; such excipients have been characterized and discussed, for examplein Karolewicz, A review of polymers as multifunctional excipients, SaudiPharm. J., 24:525-36 (2016), and references cited. In other preferredembodiments, excipients which enhance permeability (and hence improveoral bioavailability) shall be used (see Shaikh et al., PermeabilityEnhancement Techniques for Poorly Permeable Drugs: A review, J. App.Pharma. Sci., 06:34-39 (2012), and references cited). Other excipients,carriers, and diluents that can be used in the practice of the inventionshall be known to those of ordinary skill in the art.

It will be understood by those in the art that pharmaceutical excipientsuseful in the statin-cannabinoid compositions of this invention mayfurther include a binder, such as microcrystalline cellulose, colloidalsilica and combinations thereof (Prosolv 90), carbopol, providone andxanthan gum; a flavoring agent, such as sucrose, mannitol, xylitol,maltodextrin, fructose, or sorbitol; a lubricant, such as magnesiumstearate, stearic acid, sodium stearyl fumurate and vegetable basedfatty acids; and, optionally, a disintegrant, such as croscarmellosesodium, gellan gum, low-substituted hydroxypropyl ether of cellulose,sodium starch glycolate. Other additives useful in the practice of thisinvention may include plasticizers, pigments, talc, and the like. Suchexcipients, additives, and other suitable ingredients for use in thepractice of the invention are well known in the art (see, e.g., Gennaro,Remington's Pharmaceutical Sciences, 20th Ed.).

It should be apparent that the compositions of the invention are notlimited to combinations of a single statin, a single cannabinoid, and asingle carrier, diluent, or excipient alone, but also includecombinations of multiple statins, multiple cannabinoids, and/or multiplecarriers, diluents, and excipients. Pharmaceutical compositions of thisinvention thus may comprise one or more statins in combination, togetherwith one or more cannabinoids in combination, along with one or morepharmaceutically-acceptable carriers, diluents, and/or excipients.

Further, compositions within the scope of the invention should beunderstood to be open-ended and may include additional active orinactive compounds and ingredients. For instance, several combinationpreparations of a statin and another agent exist and would be understoodto be able to be used in place of a statin alone in the practice of thepresent invention. For example, simvastatin/ezetimibe could be used inplace of a statin (such as simvastatin alone), in combination with acannabinoid and a pharmaceutically-acceptable carrier, diluent, orexcipient, as could for instance simvastatin/niacin, lovastatin/niacin,or atorvastatin/amlodipine.

Routes of Administration and Dosage

Pharmaceutical dosage unit forms of the present invention are suitablefor oral or mucosal (e.g., buccal, sublingual, nasal) administration toa mammal, preferably a human. Suitable dosage forms include, forexample, tablets, pills, lozenges, sachets, cachets, elixirs,suspensions, syrups, liquid sprays or drops, soft or hard gelatincapsules, powders, pastes, gels, oral rinses, orally-dissolving films,and the like.

In certain embodiments, it is desired that the pharmaceuticalcomposition be rapidly absorbed into the bloodstream of a mammal throughthe oral mucosa (i.e., sublingually through the ventral surface of thetongue and floor of the mouth or buccally through tissues lining thecheek and gums). In one such embodiment, the statin-cannabinoidcomposition comprises an orally-disintegrating dosage form that rapidlydisintegrates/disperses in the buccal pouch or sublingual cavity withthe help of saliva (i.e., without the need for additional water).Examples of orally-disintegrating dosage forms include fast-melttablets, chewable tablets, powders, gels, orally-dissolving film strips,and lozenges. In such a form, the time of disintegration should be lessthan five minutes; or preferably less than four minutes, less than threeminutes, less than two minutes, or less than one minute; or morepreferably still, less than 30 seconds, less than 20 seconds, or lessthan 10 seconds.

The pharmaceutical compositions of the invention may be administered anddosed in accordance with good medical practice, taking into account themethod and scheduling of administration, prior and concomitantmedications and medical supplements, the clinical condition of theindividual patient and the severity of the underlying disease, thepatient's age, sex, body weight and other such factors relevant tomedical practitioners, and knowledge of the particular statin andcannabinoid used. Starting and maintenance dosage levels thus may differfrom patient to patient, for individual patients across time, and fordifferent pharmaceutical compositions, but shall be able to bedetermined with ordinary skill.

The dosage levels of active ingredients comprising thestatin-cannabinoid composition may vary depending upon the dosage formand the statin and cannabinoid chosen for administration. Thestatin-cannabinoid composition generally shall comprise a cannabinoid inan amount effective to lower the effective dose of the selected statin,or to safely allow for higher dosages of the selected statin without therisk (or with a substantially reduced risk) of severe statin-inducedadverse effects (e.g., myositis or rhabdomyolysis). For example, whenthe chosen cannabinoid enhances the bioavailability of the statin (e.g.,where the cannabinoid and statin are both substrates of the same CYPenzyme), a lower dose may be used than the commonly-prescribed dosagelevel for that statin, without loss of therapeutic effect. Additionally,it would be understood that the dose may be successfully lowered afurther amount where a larger increase in the bioavailability of thestatin is induced; for instance, where the cannabinoid is selected forgreater CYP enzyme affinity. Although dosing regimens will vary based onthe statin-cannabinoid composition chosen and the characteristics ofeach individual patient, it shall be understood that the determinationof a dosage regimen for a patient will be within the practice ofordinary skill. The following table provides one such example, for apatient switching from a regimen of atorvastatin alone to a compositionof atorvastatin and CBD:

Patient Dosing Example Atorvastatin + CBD with Atorvastatin aloneAtorvastatin + CBD greater CYP3A4 Affinity 80 mg 40 mg + 100 mg 20 mg +100 mgThis example shows that the combination of atorvastatin and CBD allowsfor a decrease in dosage of the statin of 50%; the combination ofatorvastatin and a CBD selected for greater CYP3A4 enzyme affinityallows for a decrease in dosage of the statin of 75%. The advantages ofsuch lower statin doses shall be readily apparent; for instance, thepatient who may otherwise have discontinued statin therapy because ofintolerance (thus put at increased risk of cardiovascular morbidity andmortality) may now continue statin treatment.

In general, the statin-cannabinoid composition comprises a daily dose ofbetween about 1 mg and about 80 mg of a statin. The statin compounds,when prescribed alone (as with current treatment regimens), areadministered at dosages known in the art. See, e.g., 2013 ACC/AHAguideline on the treatment of blood cholesterol to reduceatherosclerotic cardiovascular risk in adults. For example, accepteddosage ranges at the time of this filing include: Fluvastatin sodium isrecommended for a 20-80 mg daily oral dose range, preferably between 20and 40 mg/day for the majority of patients. 20 to 40 mg daily doses arepreferably taken once daily at bedtime. 80 mg daily doses is prescribedas 40 mg doses b.i.d. and recommended only for those individuals in whomthe 40 mg daily dose is inadequate to lower LDL levels satisfactorily.Atorvastatin has a recommended starting daily dose of 10 mg once daily,with an overall daily dose range of from 10 to 80 mg. Simvastatin may beadministered with a starting dose of 20 mg once a day in the evening, ora 10 mg dose per day for those requiring only a moderate reduction inLDL levels. The recommended overall daily dosage range taken as a singleevening dose is from 5 to 80 mg. Pravastatin sodium has a recommendedstarting dose of 10 or 20 mg per day, taken daily as a single dose atbedtime, with a final overall daily range of from 10 to 40 mg.Lovastatin has a recommended daily starting dosage of 20 mg per daytaken with the evening meal. The recommended final daily dosage range isfrom 10 to 80 mg per day in single or di doses. Pitavastatin, the mostrecently approved drug in this class, is administered in a dose range ofbetween 1-4 mg per day. In general, these statins are formulated in asimple oral dosage unit form. The accepted and commonly-prescribeddosage ranges for individual statins may vary over time due to newmedical evidence, which may be incorporated into new guidelines, butstandard dosage ranges shall be known or readily available to those ofordinary skill in the art. The standard dosage range for each statin isthus understood to have a lowest and highest recommended dose whenadministered alone (which may differ for dosage type and regimen, butwould nevertheless be known for each set of parameters by those ofordinary skill).

Consistent with the aim of the present invention to reducestatin-induced side effects, and to reduce statin dosages without lossof therapeutic effect, it is generally preferred that the statin dose beless than or equal to 40 mg/day. For example, in one such embodiment,the statin dose will be less than or equal to 25 mg/day. In anotherembodiment, the statin dose will be less than or equal to 20 mg/day. Inyet another embodiment, the statin dose will be less than or equal to 10mg/day. In yet another embodiment, the statin dose will be less than orequal to 5 mg/day. In yet another embodiment, the statin dose will beless than or equal to 2 mg/day. In yet another embodiment, and by way offurther example, the statin dose will be less than or equal to 1 mg/day.The statin dose selected for each individual subject shall be able to bedetermined by one of ordinary skill, based on the subject's backgroundand needs, in view of good medical practice, and in light of the aims ofthe present invention to reduce statin-induced side effects and toreduce statin dosages without loss of therapeutic effect. One ofordinary skill would further understand how to determine whether areduced dosage is as therapeutically effective as a patient's priordosage, based on the patient's medical history and current treatment.Additionally, one of ordinary skill would understand how to determinewhether the adverse effects of statin treatment are reduced for apatient, based on clinically accepted criteria. (See, e.g., Rosenson(2017); Hovingh et al., Identification and management of patients withstatin-associated symptoms in clinical practice, 245:111-17 (2016); andreferences cited.)

In certain embodiments, the statin-cannabinoid composition comprises adaily dose of between about 1 mg and about 500 mg of a cannabinoid. Toprovide for a single-dosage form of the statin-cannabinoid composition,it is generally preferred that the cannabinoid dose be less than orequal to 100 mg/day. For example, in one such embodiment, thecannabinoid dose will be less than or equal to 50 mg/day. In anotherembodiment, the cannabinoid dose will be less than or equal to 25mg/day. In another embodiment, the cannabinoid dose will be less than orequal to 20 mg/day. In another embodiment, the cannabinoid dose will beless than or equal to 10 mg/day. In another embodiment, the cannabinoiddose will be less than or equal to 5 mg/day. In another embodiment, thecannabinoid dose will be less than or equal to 2 mg/day. In yet anotherembodiment, and by way of further example, the cannabinoid dose will beless than or equal to 1 mg/day. The cannabinoid dose selected for eachindividual subject shall be able to be determined by one of ordinaryskill, based on the subject's background and needs, in view of goodmedical practice, and in light of the aims of the present invention toreduce statin-induced side effects and to reduce statin dosages withoutloss of therapeutic effect.

In certain preferred embodiments, the statin-cannabinoid compositioncomprises a daily dose of between about 1 mg and about 500 mg of a CBD.To provide for a single-dosage form of the statin-CBD composition, it isgenerally preferred that the cannabidiol dose be less than or equal to100 mg/day. For example, in one such embodiment, the CBD dose will beless than or equal to 50 mg/day. In another embodiment, the CBD dosewill be less than or equal to 25 mg/day. In another embodiment, the CBDdose will be less than or equal to 20 mg/day. In another embodiment, theCBD dose will be less than or equal to 10 mg/day. In another embodiment,the CBD dose will be less than or equal to 5 mg/day. In anotherembodiment, the CBD dose will be less than or equal to 2 mg/day. In yetanother embodiment, and by way of further example, the CBD dose will beless than or equal to 1 mg/day. The CBD dose selected for eachindividual subject shall be able to be determined by one of ordinaryskill, based on the subject's background and needs, in view of goodmedical practice, and in light of the aims of the present invention toreduce statin-induced side effects and to reduce statin dosages withoutloss of therapeutic effect. In determining dosages, one also wouldunderstand that the effective dose of CBD may be determined in part inview of the biphasic dose curve for CBD (i.e., a U-shaped dose-responsecurve in which efficacy is optimal between low and high doses).

Optionally, the daily dose of statin-cannabinoid composition may beadministered as a single dose (i.e., one time per day), or divided intomultiple doses (e.g., two, three, or more doses) over the course of aday.

In another embodiment the pharmaceutical composition of the presentinvention may be prepared, packaged or sold in a titratable dosage form.The term “titrate” is defined as meaning that the patient is providedwith a medication that is in such a form that smaller doses than theunit dose can be taken. A “unit dose” is defined as a maximum dose ofmedication that can be taken at any one time or within a specifieddosage period. Titration of doses is beneficial to the patient as theyare able to increase the dose incrementally until the drug isefficacious. It is understandable that not all patients will requireexactly the same dose of medication, for example patients of arelatively larger build or faster metabolism may require a higher dose.Different patients may also present with different degrees of complaintsand as such may require larger or smaller doses in order to treat thecomplaint effectively. The benefits of a titratable dosage form over astandard dosage form, which would have to be split into a partial dose,are therefore evident.

In some embodiments, the pharmaceutical composition of the presentinvention may be prepared, packaged or sold in a formulation suitablefor oral digestive administration. Such formulations may, for example,be in solid dosage form such as pills, tablets, capsules, or may be inliquid form. In some preferred embodiments, the pharmaceuticalcomposition comprises an effervescent dosage form such as aneffervescent tablet. In other preferred embodiments, the composition isa multi-layer tablet. Methods of preparing formulations suitable fororal administration include, for example, those described inWO2005/034908A2, and references cited.

In other embodiments, the pharmaceutical composition of the presentinvention may be prepared, packaged or sold in a formulation suitablefor buccal administration. Such formulations may, for example, be in theform of buccal tablets, bioadhesive particles, wafers, lozenges,medicated chewing gums, adhesive gels, patches, films, a paste, anointment, or an aerosol.

In yet other embodiments, the pharmaceutical composition of the presentinvention may be prepared, packaged or sold in a formulation suitablefor sublingual administration. Such formulations may, for example, be inthe form of sublingual tablets, drops, films, sprays or aerosols, orlozenges.

Preparation of statin formulations suitable for buccal or sublingualadministration has been described in, e.g., U.S. Pat. App. Nos.2015/0328142A1, US2003/0162827A1, and PCT/US2002/021287.

Notably, buccal or sublingual administration allows fornear-instantaneous adsorption of the statin into the blood streamthrough the oral mucosa in contrast to conventional oral administration,which typically takes from one to two hours after administration by theoral digestive route. Moreover, the buccal and sublingual formulationsof the present invention allow for even lower dosages of statin to begiven without loss of therapeutic effect, because delivery (of both thestatin and the cannabinoid) bypasses GI and first pass metabolism.

Administration of the pharmaceutical compositions of the invention, suchas the embodiments described above, are therefore advantageously used totreat hypercholesterolemia and atherosclerosis in a subject, as well asto treat or prevent myositis, rhabdomyolysis or statin-associatedmyopathy in a subject.

The invention claimed is:
 1. A pharmaceutical composition in unit dosage form for once daily dosing, useful in treating a patient with a lipid disorder, which consists essentially of a statin-cannabidiol combination of: (a) a reduced daily dosage amount of a statin; and (b) less than or equal to 500 mg of a cannabidiol; together with a pharmaceutically acceptable carrier, diluent, or excipient; wherein the reduced daily dosage amount of the statin is less than the lowest standard daily dosage amount for the statin when taken alone; and wherein the pharmaceutical composition is formulated for oral or mucosal administration and the statin-cannabidiol combination confers a synergistic effect compared to the statin and the cannabidiol administered alone in the same amounts, said synergistic effect responsible for the reduced daily dosage amount of the statin without loss of therapeutic effect, and wherein the statin is atorvastatin.
 2. The pharmaceutical composition of claim 1, wherein the atorvastatin is present in the unit dosage form in an amount of between 5-10 mg.
 3. The pharmaceutical composition of claim 1, wherein the atorvastatin is present in the unit dosage form in an amount of between 2-5 mg.
 4. The pharmaceutical composition of claim 1, wherein the statin is present in the unit dosage form in an amount of between 1-2 mg.
 5. The pharmaceutical composition of claim 1, wherein the atorvastatin is present in the unit dosage form in an amount of less than 1 mg.
 6. The pharmaceutical composition of claim 1, wherein the unit dosage form is suitable for oral administration, and atorvastatin and the cannabidiol both undergo first-pass metabolism after administration.
 7. The pharmaceutical composition of claim 1, wherein the unit dosage form is suitable for buccal or sublingual administration.
 8. A pharmaceutical composition for once daily dosing, useful in treating a patient with a lipid disorder, which consists essentially of a statin-cannabidiol combination of therapeutically effective amounts of: (a) a reduced daily dosage amount of a statin; and (b) a cannabidiol; wherein the reduced daily dosage amount of the statin is less than the lowest standard daily dosage amount for the statin when taken alone; and wherein the pharmaceutical composition is formulated for oral or mucosal administration and the statin-cannabidiol combination confers a synergistic effect compared to the statin and the cannabidiol administered alone in the same amounts, said synergistic effect responsible for the reduced daily dosage amount of the statin without loss of therapeutic effect, and wherein the statin is atorvastatin.
 9. The pharmaceutical composition of claim 8, wherein the reduced daily dosage amount of the atorvastatin is no greater than 50% of the lowest standard daily dosage amount for the atorvastatin when taken alone.
 10. The pharmaceutical composition of claim 8, wherein the reduced daily dosage amount of atorvastatin is no greater than 25% of the lowest standard daily dosage amount for atorvastatin when taken alone.
 11. The pharmaceutical composition of claim 8, wherein the atorvastatin and the cannabidiol are both substrates of the same CYP enzyme, and the atorvastatin and the cannabidiol both undergo first-pass metabolism after administration by said CYP enzyme.
 12. The pharmaceutical composition of claim 8, wherein the cannabidiol has been selected for greater affinity for a CYP enzyme.
 13. A method of treating a medical condition in a human in need of such treatment, the method comprising administering in combination to the human a synergistically and therapeutically effective amount of atorvastatin and a cannabidiol, and wherein the medical condition is selected from the group consisting of a dysregulation of cholesterol metabolism, myositis, rhabdomyolysis, and statin-associated myopathy.
 14. The method of claim 13 wherein the medical condition is hypercholesterolemia.
 15. The method of claim 13 wherein the medical condition is atherosclerosis. 